Background Meningiomas are the most frequently occurring primary intracranial tumours in adults. Surgical removal can only be curative by complete resection; however surgical access can be challenging due to anatomical localization and local invasion of bone and soft tissues. Several intraoperative techniques have been tried to improve surgical resection, including intraoperative fluorescence guided imaging; however, no meningioma-specific (fluorescent) targeting has been developed yet. Here, we aimed to identify the most promising biomarkers for targeted intra-operative fluorescence guided meningioma surgery. Methods One hundred forty-eight meningioma specimens representing all meningioma grades were analysed using immu- nohistochemistry (IHC) on tissue microarrays (TMAs) to determine expression patterns of meningioma biomarkers epi- thelial membrane antigen (EMA), platelet-derived growth factor β (PDGF-β), vascular endothelial growth factor α (VEGF-α), and somatostatin receptor type 2 (SSTR-2). Subsequently, the most promising biomarker was selected based on TArget Selection Criteria (TASC). Marker expression was examined by IHC in 3D cell culture models generated from freshly resected tumour material. Results TMA-IHC showed strongest staining for SSTR-2. All cases were positive, with 51.4% strong/diffuse, 30.4% moderate/diffuse and only 18.2% focal/weak staining patterns. All tested biomarkers showed at least weak positivity in all meningiomas, regardless of WHO grade. TASC analysis showed that SSTR-2 was the most promising target for fluorescence guided imaging, with a total score of 21 (out of 22). SSTR-2 expression was determined on original patient tumours and 3D cultures of three established cultures. Conclusions SSTR-2 expression was highly sensitive and specific in all 148 meningiomas, regardless of WHO grade. According to TASC analysis, SSTR-2 is the most promising receptor for meningioma targeting. After establishing in vitro meningioma models, SSTR-2 cell membrane expression was confirmed in two of three meningioma cultures as well. This indicates that specific fluorescence in an experimental setting can be performed for the further development of targeted fluorescence guided meningioma surgery and near-infrared fluorescent tracers B. M. Dijkstra and A. Motekallemi contributed equally to this work. targeting SSTR-2. * R. J. M. Groen Keywords Intracranial meningioma Fluorescence guided firstname.lastname@example.org . . surgery Intraoperative imaging Somatostatin receptor subtype 2 Biomarker Department of Neurosurgery, University Medical Center Groningen, University of Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB Groningen, The Netherlands Abbreviations Department of Neurosurgery, University Medical Center Münster, EMA Epithelial membrane antigen Münster, Germany IHC Immunohistochemistry Department of Pathology, University Medical Center Groningen, PDGFR-β Platelet-derived growth factor receptor beta University of Groningen, Groningen, The Netherlands SSTR-2 Somatostatin receptor type 2 Department of Surgery, Nuclear Medicine and Molecular Imaging T/N Tumour-to-normal tissue ratio and Intensive Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands TASC TArget Selection Criteria TMA Tissue microarray Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands VEGF-α Vascular endothelial growth factor A 1540 Acta Neurochir (2018) 160:1539–1546 Introduction available for analysis. All patient data were anonymized ac- cording to the regulations of the Medical Ethical Research Meningiomas are the most frequently occurring intracranial Committee of the University Medical Center Groningen. tumours in adults, accounting for approximately one third of Meningioma samples were examined using tissue microar- cases . They are classified by the World Health rays (TMAs). TMA sections were deparaffinised with xylene, Organization (WHO) into three malignancy grades with 15 rehydrated in ethanol, and rinsed in distilled water. After anti- histologic subtypes . Treatment is usually only curative gen retrieval with a Tris-EDTA or Tris-HCl buffer, endogenous with complete surgical resection [6, 50] and aims for both peroxidase was blocked for 30 min using a 0.1% H O PBS 2 2 complete tumour removal and preservation of neurological solution. Respective antibody staining was performed at room function [29, 55]. Although mostly benign and slow growing, temperature. The selected primary antibodies of interest were all meningiomas can pose surgical challenges due to anatom- anti-EMA (mouse monoclonal, Dako), anti-PDGFR-β (rabbit ical localization and local invasion of bone and soft tissues, polyclonal, Santa Cruz), anti-VEGF-α (rabbit polyclonal, leading to residual tumour tissue. Incomplete resection is one Santa Cruz) and anti-SSTR-2 (rabbit monoclonal, Epitomics). of the risk factors for recurrence . We used normal cerebellar and anterior pituitary tissue as pos- One of the proposed techniques to facilitate resection is intra- itive controls. Additionally, we omitted the primary antibody operative fluorescence-guided imaging. Several fluorescent dyes and used IgG controls. Secondary and tertiary antibody staining (5-aminolevulinic acid, fluorescein, and indocyanine green) have was performed for 30 min. All sections were subjected to a 3,3- been tried [1, 10, 14, 25, 33]; however, evidence regarding the diaminobenzidine solution for 10 min and finally counter- benefit of applying these dyes is unavailable. Furthermore, fluo- stained with haematoxylin for 2 min, dehydrated in ethanol, rescent dyes currently lack specificity. The concept of targeted cleared, mounted and cover slipped. fluorescence is appealing, due to high sensitivity and specificity For immunohistochemical (IHC) evaluation, TMA sections rates. Identification of meningioma-specific biomarkers is a first were scanned with an ultra-resolution digital scanner and essential step in this concept. Comparable targeted fluores- ScanScope CS®, Aperio® with × 20 image magnification cent techniques have been established in other tumour types, e.g. and evaluated with Aperio ImageScope® software. Each tissue in ovarian carcinoma [17, 53] and peritoneal metastases of colo- core of the TMA section was scored using the following scor- rectal carcinomas  targeting αvβ3-integrin or folate receptor ing method: negative, (0); weak/focal staining, (1); moderate/ α and VEGF-α, respectively. For the development of a similar diffuse staining, (2); strong/diffuse staining, (3). Two authors approach in meningioma surgery, various biomarkers have been (AM and WFD) independently evaluated tissue cores and in suggested, including epithelial membrane antigen (EMA), case of discrepant scores, consensus was reached by way of platelet-derived growth factor beta (PDGF-β), vascular endothe- discussion between both evaluators. Cores were regarded as lial growth factor A (VEGF-α), and somatostatin receptor type 2 non-informative and consequently dismissed when > 50% tis- (SSTR-2) [3, 5, 9, 11, 12, 16, 19, 21, 28, 30, 32, 38, 39, 43–45, sue was lost or presented inappropriate amounts of collagen 48, 52, 56]. However, the suitability of these markers for staining. Tumour specimens which were represented by less fluorescence-guided imaging meningioma surgery has not yet than two complete cores were excluded. A mean score was been investigated. calculated for each specimen and specimens with an average In this study, we aimed to make a step-wise approach: (1) score of 1 were considered positive, whereas specimens with a identifying meningioma-specific candidate biomarkers mean score of ≥ 2 were summarized as Bhigh score^. (EMA, PDGF-β, VEGF-α and SSTR-2); (2) selecting the most promising tumour-specific marker; and (3) confirming Statistical analysis its expression in in vitro cultures derived from fresh meningi- oma specimens. All statistical analyses were performed using IBM® SPSS® Statistics 20. Spearman rank-order correlation was used to find correlation between targets and WHO classifications. Methods and materials All reported P values were two sided and a value of P ≤ 0.05 was considered as statistically significant. Part 1: identifying meningioma-specific candidate biomarkers Part 2: selecting the most promising tumour-specific marker Specimens of previously untreated, primary intracranial me- ningiomas resected between January 2006 and December To investigate the usefulness of these markers for intra- 2010 were retrospectively analysed for the expression of four operative fluorescence-guided imaging, the TArget Selection potential biomarkers (i.e. EMA, PDGF-β,VEGF-α and Criteria (TASC)  were utilized for the selection of the most SSTR-2). A total number of 148 meningioma specimens were promising targets, as depicted in Table 1. Acta Neurochir (2018) 160:1539–1546 1541 Table 1 TASC scoring system Criteria Characteristics Score I Extracellular protein localization Bound to cell surface (receptor) 5 In close proximity of tumour cell 3 II Diffuse upregulation through tumour 4 tissue III Tumour-to-normal ratio > 10 3 IV Percentage upregulation in patients > 90% 6 70–89% 5 50–69% 3 10–49% 0 V Previouslysuccessfullyimaged invivo 2 VI Enzymatic activity 1 VII Internalization 1 Maximum: 22 Potential target ≥ 18 Part 3: confirming expression in in vitro cultures Kaiser’s glycerin for microscopic examination using a Leica DM 3000 microscope. Meningioma 3D cell culture models were established to pro- vide an accurate model for the disease [13, 24]. Surgical left- over fresh tumour tissue was washed with ice-cold PBS and mechanically dissociated. After adding 15 to 20 ml accutase, Results tissue incubated for 30 min at room temperature. The suspen- sion was passed through a 70-μm cell strainer to procure sin- Part 1: identifying meningioma-specific candidate gle cells and pelleted. Cells were seeded in T75 flasks with biomarkers medium containing DMEM/F12 supplemented with 2% B27, 20 ng/ml EGF, 20 ng/ml bFGF , and 2% pen/strep. Patient characteristics For IHC analyses, 3D cultures were dissociated with accutase and cytospun. Subsequently, cells were fixated with Patient and tumour characteristics are summarized in Table 2. 4% formaldehyde, washed with PBS and underwent a The age at surgery ranged from 4 to 79 years. Tumour spec- blocking step with 1% H O in PBS for 10 min. Cells were imens were obtained from 52 male and 96 female patients. 2 2 then incubated with anti-SSTR-2 (1:100; MAB4224, R&D Our study revealed 124 WHO I (83.8%), 22 WHO II systems) for 1 h, followed by incubation of the corresponding (14.9%) and 2 WHO III (1.4%) meningiomas. All tested bio- secondary and tertiary antibodies diluted at 1:50 in PBS with markers showed at least weak positivity in all meningiomas, 1% BSA and 1% AB serum for 30 min. Lastly, cells were regardless of WHO grade. No association was found between incubated with 5% 3-amino-9-ethylcarbazole diluted in ace- WHO grade and the expression rates of the potential targets tate buffer with 0.1% hydrogen peroxide for 10 min, counter- using Spearman rank order correlation (Table 3). stained with haematoxylin for 2 min, and mounted with Table 3 Correlation between target expression and WHO grades Table 2 Patient and tumour specimen characteristics Target Spearman correlation (p value) Men Women EMA Percent (n (%)) 52 (35.1) 96 (64.9) Age (years) (mean (range)) 47.2 (4.4–79.8) 52.4 (4.2–77.5) VEGF-α Meningioma grade (n (%*)) WHO I 38 (25.7) 86 (58.1) PDGFR-β WHO II 12 (8.1) 10 (6.8) WHO III 2 (1.4) 0 (0.0) SSTR-2 *Percentage of all meningiomas 1542 Acta Neurochir (2018) 160:1539–1546 Table 4 Summary of IHC results Target Valid Weak/focal Moderate/ diffuse Strong/diffuse High score* (%) cores (%) (%) (%) EMA 148 16 (10.8) 113 (76.4) 19 (12.8) 132 (89.2) VEGF-α 145 45 (31.0) 93 (64.1) 7 (4.8) 100 (69.0) PDGFR-β 147 34 (23.1) 107 (72.8) 6 (4.1) 113 (76.9) SSTR-2 148 27 (18.2) 45 (30.4) 76 (51.4) 121 (81.8) Shown percentages are valid ratios for the respective target *Defined as moderate/diffuse or strong/diffuse staining Target expression in TMA sections VEGF-α seem to be high potential targets with TASC scores of 20, 20 and 18, respectively. Both cerebellar and anterior pituitary tissue showed SSTR-2- positivity. Additionally, white matter in the cerebellar tissue Part 3: confirming expression in in vitro cultures was SSTR-2 negative, as expected. Omission of the primary antibody revealed no SSTR-2 staining and aspecific binding Generating meningioma cultures with IgG was not observed. TMA-IHC results are summarized in Table 4.Ofall TMA In vitro cultures were established to further explore the poten- meningioma specimens (588), 99.8% was IHC-positive for tial of SSTR-2 as a meningioma-specific marker in a transla- the investigated targets with at least two or more valid tissue tional model. After processing the freshly resected material, cores. The number of non-informative/invalid cores was low 11 of 22 cultures (50%) generated 3D cultures after 7 days for PDGFR-β (0.7%) and VEGF-α (2.0%) and all cores for (Fig. 2, top panel). However, growth decreased after three to EMA and SSTR-2 were valid. The IHC staining score for four passages. A selection of three cultures named MgG24, SSTR-2 was the most robust, resulting in positivity for MgG26 and MgG27 was characterized in more detail. These SSTR-2 in all specimen: moderate/diffuse or strong/diffuse cultures originated from three female patients with a mean age positivity in 81.8% (Bhigh score^) and focal/weak positivity of 65.7 years (range 60–77; SD 9.8). All meningiomas were in only 18.2% of all cases. Representative examples illustrat- WHO grade I, with one transitional and two meningothelial ing SSTR-2 expression are shown in Fig. 1. meningiomas (Fig. 2, middle panel). Two meningiomas were located at the convexity and one at the skull base (Fig. 2, bottom panel). Part 2: selecting the most promising tumour-specific marker SSTR-2 expression in in vitro meningioma cultures The selected markers were evaluated using TASC based on IHC-TMA results (Table 5). Using these criteria, SSTR-2 is SSTR-2 expression was determined on original patient tu- the most promising target for intra-operative use with a total mours and 3D cultures of the three established cultures. All TASC score of 21. In addition, EMA, PDGFR-β and patient tumours were strongly positive for SSTR-2 at the cell Fig. 1 Representative images of SSTR-2 stained TMA-IHC cores and scoring approach. Shown are weak/focal (left), moderate/diffuse (middle), and strong/diffuse (right) staining patterns Acta Neurochir (2018) 160:1539–1546 1543 Table 5 Target selection by applying TASC TASC I II III IV V VI VII Score item Localization Expression T/N Upregulation In vivo Enzymatic Internalization Target pattern* ratio in patients* imaging activity (%) EMA Transmembrane Diffuse High 100 Yes [34, 49]ND ND 20 VEGF-α Secreted Diffuse High 100 Yes [35, 36, 47]ND ND 18 PDGFR-β Transmembrane Diffuse High 100 Yes ND ND 20 SSTR-2 Transmembrane Diffuse High 100 Yes [21, 23, 52]YesND 21 ND, not described; T/N ratio, tumour-to-normal tissue ratio *Results based on this study Expression patterns are considered Bdiffuse^, if moderate/diffuse or strong/diffuse staining is present in more than 66% of included cases membrane (Fig. 3, top panel). However, of the dissociated 3D are (equally) positive in both cultures: some cells show no or cultures, only MgG24 and MgG26 are SSTR-2 positive with a weak SSTR-2 positivity, whereas in other cells, the staining is cell membranous staining. It should be noted that not all cells strongly positive (Fig. 3,bottom panel). Fig. 2 Top panel shows micrographs of 3D meningioma cultures with × formation into a sphere. H&E stained tumour samples confirmed the 10 magnification. Middle panel depicts micrographs of H&E stained diagnosis of meningioma in all three cases. MRI scans revealed original patient tumour at × 40 magnification. Bottom panel are meningiomas at the convexity and skull base gadolinium-enhanced MRI scans. 3D cultures showed aggregated cell 1544 Acta Neurochir (2018) 160:1539–1546 Fig. 3 Top panel depicts micrographs from primary tumour stained for magnification. Patient material showed SSTR-2 membrane staining in SSTR2 at × 10 magnification. Bottom panel shows micrographs of all tumours. Two of three dissociated 3D cultures revealed SSTR-2 dissociated cells cultured as 3D and stained for SSTR2 at × 40 positive membranous staining in a fraction of cells Discussion imaging. One culture was SSTR-2 negative, which may be due to a technical issue with reduced culture viability. The first aim of this study was to identify the expression pat- Indeed, the original patient tumour was SSTR-2 positive. tern of a series of preselected markers (EMA, PDGF-β, Further research is warranted to investigate this issue further. VEGF-α and SSTR-2) in meningiomas using TMA-IHC, As far as we know, this is the first time that the expression which resulted in the analysis of a large collection of tested SSTR-2 has been determined in in vitro meningioma cultures meningioma samples. We confirmed previous findings re- using IHC. Several limitations became apparent when using garding meningioma biomarkers [3, 5, 9, 11, 12, 16, 19, 21, this model. The cultures could be subcultured for a limited 28, 30, 32, 38, 39, 43–45, 48, 52, 56]. All investigated markers number of passages: cell growth decreased after three to four tested positive in all meningiomas, regardless of WHO grade. passages, similar to a previous report . Moreover, the gen- However, SSTR-2 expression was especially robust with a erated in vitro models are all originating from WHO grade I Bhigh score^ in 81.8% of all cases. SSTR-2 was also highly meningiomas. Although patients with high grade lesions may specific and sensitive. These findings are in line with previous benefit the most from intraoperative imaging, WHO I menin- studies [12, 30, 48]. Subsequently we focused on the second giomas are still a representable model as SSTR-2 is expressed aim of this study, namely, identifying the most promising in all meningiomas, regardless the grade [30, 48]. tumour-specific marker for intraoperative application. The present study is an essential first step towards the de- Applying TASC, SSTR-2 was found to be superior when velopment of meningioma-specific intraoperative fluorescence- compared to the other three biomarkers. Although TASC guided imaging. Future steps should consist of binding studies was initially developed for target selection in colorectal cancer with fluorescent dyes (preferably near-infrared dyes, such as and has not yet been validated in other tumours, the principle IRDye 800CW) with SSTR-2 analogues (e.g. octreotate). is also applicable to other tumour types as it is based on bio- These have already been used in targeted therapy for recurrent marker characteristics and not on a specific tumour type. This meningiomas [2, 8, 42] and their application in theranostics and tool (TASC) is the first structured method to determine the PET-scanning has been demonstrated [19, 21, 52]. IRDye 800 suitability of a biomarker for intraoperative imaging. As a CW has undergone a microdosing study  and has been major advantage, TASC provides an objective score by con- applied in various clinical trials . Further validation is need- sidering available evidence. ed by testing a target-directed imaging tool in vitro for proof of The potential of SSTR-2 was analysed in a translational concept, andsubsequentlyininvivoanimalmodelsusingxe- model using newly generated patient-derived 3D meningioma nograft mouse models. Animal models have been successfully cultures. In two of three tested cultures, SSTR-2 expression applied previously, using fresh patient-derived material [20, 31, was present at the cell membrane, emphasizing the possibility 41, 51] or immortalized meningioma cell lines [4, 7, 40, 41], of SSTR-2 as a potential target for fluorescence guided with higher grade meningiomas yielding a higher success rate. 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Acta Neurochirurgica – Springer Journals
Published: Jun 1, 2018
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